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Homeobox genes d11–d13 and a13 control mouse autopod cortical bone and joint formation
- Source :
- The Journal of clinical investigation
- Publication Year :
- 2010
- Publisher :
- American Society for Clinical Investigation, 2010.
-
Abstract
- The molecular mechanisms that govern bone and joint formation are complex, involving an integrated network of signaling pathways and gene regulators. We investigated the role of Hox genes, which are known to specify individual segments of the skeleton, in the formation of autopod limb bones (i.e., the hands and feet) using the mouse mutant synpolydactyly homolog (spdh), which encodes a polyalanine expansion in Hoxd13. We found that no cortical bone was formed in the autopod in spdh/spdh mice; instead, these bones underwent trabecular ossification after birth. Spdh/spdh metacarpals acquired an ovoid shape and developed ectopic joints, indicating a loss of long bone characteristics and thus a transformation of metacarpals into carpal bones. The perichondrium of spdh/spdh mice showed abnormal morphology and decreased expression of Runt-related transcription factor 2 (Runx2), which was identified as a direct Hoxd13 transcriptional target. Hoxd11–/–Hoxd12–/–Hoxd13–/– triple-knockout mice and Hoxd13–/–Hoxa13+/– mice exhibited similar but less severe defects, suggesting that these Hox genes have similar and complementary functions and that the spdh allele acts as a dominant negative. This effect was shown to be due to sequestration of other polyalanine-containing transcription factors by the mutant Hoxd13 in the cytoplasm, leading to their degradation. These data indicate that Hox genes not only regulate patterning but also directly influence bone formation and the ossification pattern of bones, in part via Runx2.
- Subjects :
- medicine.medical_specialty
Long bone
Cartilage metabolism
Biology
Bone and Bones
Mice
03 medical and health sciences
0302 clinical medicine
Internal medicine
medicine
Animals
Hox gene
Alleles
030304 developmental biology
Mice, Knockout
0303 health sciences
Ossification
Extremities
General Medicine
medicine.disease
Synpolydactyly
Cell biology
Cartilage
Endocrinology
medicine.anatomical_structure
HOXD13
embryonic structures
Homeobox
Cortical bone
medicine.symptom
Peptides
030217 neurology & neurosurgery
Signal Transduction
Transcription Factors
Research Article
Subjects
Details
- ISSN :
- 00219738
- Volume :
- 120
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....bfd9aea61d47481466b45d426a79967e
- Full Text :
- https://doi.org/10.1172/jci41554